The Set1 histone methyltransferase protein was first identified in yeast as part of the Set1/COMPASS histone methyltransferase complex, which methylates histone H3 at Lys4 and functions as a transcriptional co-activator. While yeast contain only one known Set1 protein, six Set1-related proteins exist in mammals: SET1A, SET1B, MLL1, MLL2, MLL3, and MLL4, all of which assemble into COMPASS-like complexes and methylate histone H3 at Lys4. These Set1-related proteins are each found in distinct protein complexes, all of which share the common subunits WDR5, RBBP5, ASH2L, CXXC1 and DPY30. These subunits are required for proper complex assembly and modulation of histone methyltransferase activity. MLL1 and MLL2 complexes contain the additional protein subunit, menin. Like yeast Set1, all six Set1-related mammalian proteins methylate histone H3 at Lys4. MLL translocations are found in a large number of hematological malignancies, suggesting that Set1/COMPASS histone methyltransferase complexes play a critical role in leukemogenesis.